"To patent or not to patent? the case of Novartis' cancer drug Glivec in India".
Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of chronic myeloid leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec's patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable. The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: "India", "Novartis", "Glivec", "Patent", "Novartis Case", and "Supreme Court of India". The data sources were interpreted and analyzed according to the authors' own prior knowledge and understanding of the exigencies of the TRIPS Agreement. This case illuminates how India is interpreting international law to fit domestic public health needs. The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India's decision may affect the interpretation of the article of the TRIPS Agreement, which states members shall be free to determine the appropriate method of implementing the provisions of this Agreement within their own legal system and practice.


[Therapeutic trial of beta 2-adrenergic agonist clenbuterol in muscular dystrophies].
We report the outcome of trial of clenbuterol in four adult muscular dystrophy patients. One patient with Becker type, one with Miyoshi type, and two with facioscapulohumeral type were given clenbuterol (30 or 40 micrograms/day) for 6 to 18 months. We evaluated muscle strength of isometric contraction, grip and pinch power, compound muscle action potentials of intrinsic muscles, vital capacity, urinary creatinine excretion, and muscle CT. Power and volume of well preserved muscles increased mostly, while those of atrophic muscles did not improve. Vital capacity increased in two patients. No improvement of ADL was observed presumably because ADL was mainly determined by the most atrophic and weak muscles. Irrespective of type of muscular dystrophy, administration of clenbuterol may be beneficial in early stage of the disease.


Dacus oleae microbial symbionts.
Dacus oleae (Gmelin), which is a major insect pest of the olive tree, is closely associated during all developmental stages with a bacterial symbiont. This review describes the localization and transmission of the symbiont, the attempts made to isolate, cultivate and characterize it, and the host-symbiont interactions.


Computational insights into the charge relaying properties of β-turn peptides in protein charge transfers.
Density functional theory calculations suggest that β-turn peptide segments can act as a novel dual-relay elements to facilitate long-range charge hopping transport in proteins, with the N terminus relaying electron hopping transfer and the C terminus relaying hole hopping migration. The electron- or hole-binding ability of such a β-turn is subject to the conformations of oligopeptides and lengths of its linking strands. On the one hand, strand extension at the C-terminal end of a β-turn considerably enhances the electron-binding of the β-turn N terminus, due to its unique electropositivity in the macro-dipole, but does not enhance hole-forming of the β-turn C terminus because of competition from other sites within the β-strand. On the other hand, strand extension at the N terminal end of the β-turn greatly enhances hole-binding of the β-turn C terminus, due to its distinct electronegativity in the macro-dipole, but does not considerably enhance electron-binding ability of the N terminus because of the shared responsibility of other sites in the β-strand. Thus, in the β-hairpin structures, electron- or hole-binding abilities of both termini of the β-turn motif degenerate compared with those of the two hook structures, due to the decreased macro-dipole polarity caused by the extending the two terminal strands. In general, the high polarity of a macro-dipole always plays a principal role in determining charge-relay properties through modifying the components and energies of the highest occupied and lowest unoccupied molecular orbitals of the β-turn motif, whereas local dipoles with low polarity only play a cooperative assisting role. Further exploration is needed to identify other factors that influence relay properties in these protein motifs.


An Insight into Aging, Senescence, and Their Impacts on Wound Healing.
Cellular senescence has been found to have beneficial roles in development, tissue regeneration, and wound healing. However, in aging senescence increases, and the ability to properly repair and heal wounds significantly declines across multiple tissues. This age-related accumulation of senescent cells may cause loss of tissue homeostasis leading to dysregulation of normal and timely wound healing processes. The delays in wound healing of aging have widespread clinical and economic impacts, thus novel strategies to improve wound healing in aging are needed and targeting senescence may be a promising area.


[Surgical management of atrio-ventricular septal defects: a single-institutional experience].
Atrio-ventricular septal (AVSD) defects include a variable spectrum of congenital malformations with different forms of clinical presentation. We report the surgical results, from a single institution, with this type of congenital cardiac malformation. Patients with hypoplasia of one of the ventricles were excluded from this analysis. Between November of 1998 and June of 2005, 49 patients with AVSD were operated on by the same team and in the same department. The average age was 37.3 months (medium 6 months) and 31 patients were female. In 38 patients (78%) an inter-ventricular communication was present (AVSD-complete) and of these, 26 were of the type A of Rastelli, being 13 of type B or C. The age for defect correction of the complete form was of 5.5 months, palliative surgery was not carried out on any of the patients. Associated lesions included: Down's syndrome in 22 patients (45%), patent arterial duct in 17 patients (35%), severe AV regurgitation in 4 patients (8%), tetralogy of Fallot in two (4%) and sub-aortic stenosis in one patient (2%). Pre-operatively 10 patients presented severe congestive heart failure and two were mechanically ventilated. Complete biventricular correction was carried out in all patients. The average time on bypass (ECC) was 74.1+/-17.5 min. and time of aortic clamping was 52.0+/-12.9 min. The complete defects were corrected by the double patch technique, and in all patients the mitral cleft was closed, except in two with single papillary muscle. There was no intra-operative mortality, but hospital mortality was 8%(4 patients), due to pulmonary hypertension crises, in the first 15 post-operative days. The mean ventilation time was of 36.5+/-93 hours (medium 7 h) and the average ICU stay was of 4.3+/-4.8 days (medium 3 days). The minimum follow-up period is 1 month and the maximum is 84 months (medium 29.5 months), during which time 4 re-operations (8%) took place: two for residual VSD's and two for mitral regurgitation. There was no mortality at re-do surgery. At follow up there was residual mitral regurgitation, mild in 17 patients and moderate in two. Four other patients presented with minor residual defects. The complete correction of AVSD can be carried out with acceptable results, in a varied spectrum of anatomic forms and of clinical severity. Despite the age of correction, for the complete forms, predominantly below 12 months, pulmonary hypertension was the constant cause for post operative mortality. Earlier timing of surgery and stricter peri-operative control might still improve results.


Beauty and the beholder: the role of visual sensitivity in visual preference.
For centuries, the essence of aesthetic experience has remained one of the most intriguing mysteries for philosophers, artists, art historians and scientists alike. Recently, views emphasizing the link between aesthetics, perception and brain function have become increasingly prevalent (Ramachandran and Hirstein, 1999; Zeki, 1999; Livingstone, 2002; Ishizu and Zeki, 2013). The link between art and the fractal-like structure of natural images has also been highlighted (Spehar et al., 2003; Graham and Field, 2007; Graham and Redies, 2010). Motivated by these claims and our previous findings that humans display a consistent preference across various images with fractal-like statistics, here we explore the possibility that observers' preference for visual patterns might be related to their sensitivity for such patterns. We measure sensitivity to simple visual patterns (sine-wave gratings varying in spatial frequency and random textures with varying scaling exponent) and find that they are highly correlated with visual preferences exhibited by the same observers. Although we do not attempt to offer a comprehensive neural model of aesthetic experience, we demonstrate a strong relationship between visual sensitivity and preference for simple visual patterns. Broadly speaking, our results support assertions that there is a close relationship between aesthetic experience and the sensory coding of natural stimuli.


A review of standard and newer treatment strategies in hepatitis C.
Chronic infection with hepatitis C virus (HCV) is common, but underdiagnosed and undertreated worldwide. The most important treatment outcome in HCV is sustained virological response (SVR), due to its impact on reducing the risks of liver-related mortality, hepatocellular carcinoma, and hepatic decompensation. The degree of baseline liver disease, IL28B genotype, and HCV genotype are important determinants of response to treatment, and SVR rates less than 50% can be expected for persons with genotype 1 receiving standard peginterferon with ribavirin. The rates are even lower when cirrhosis is present. There is little evidence supporting improved outcomes with peginterferon and ribavirin retreatment, and escalation of ribavirin dosage leads to an increased risk of adverse events. Introduction of the protease inhibitors, boceprevir and telaprevir, has resulted in SVR rates between 67% and 79% when used as part of a triple therapy regimen, which has become the standard of care for those with genotype 1 HCV. More work is needed to develop strategies to further improve treatment outcomes, and ideally to develop a vaccine to prevent the development of chronic HCV.


Evolution of neuroglia.
The evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed of electrically excitable neuronal networks connected by chemical synapses and nonexcitable glial cells that provide for homeostasis and defense. The evolution of neuroglia began with the emergence of the centralized nervous system and proceeded through a continuous increase in their complexity. In the primate brain, especially in the brain of humans, the astrocyte lineage is exceedingly complex, with the emergence of new types of astroglial cells possibly involved in interlayer communication and integration.


Novel Use of Proteomic Profiles in a Convex-Hull Ensemble Classifier to Predict Gynecological Cancer Patients' Susceptibility to Gastrointestinal Mucositis as Side Effect of Radiation Therapy.
Whole-pelvis radiation therapy is common practice in the post-surgical treatment of cervical and endometrial cancer. Gastrointestinal mucositis is an adverse side effect of radiation therapy, and is a primary concern in patient management. We investigate whether proteomic information obtained from blood samples drawn from patients scheduled to receive radiation therapy for gynecological cancers could be used to predict which patients are most susceptible to radiation-induced gastrointestinal mucositis, in order to improve the individualization of radiation therapy. We use 132 proteins measured on 17 gynecological cancer patients in a convex-hull-based, selective-voting ensemble classifier to classify each patient into one of two classes: patients who would not (class 1) or would (class 2) develop gastrointestinal mucositis. We employ 20 repetitions of 10-fold cross-validation to measure classification accuracy. We achieved a 95% confidence interval on average prediction accuracy of (0.711, 0.771) using pre-radiation proteomic profiles to predict which patients would experience gastrointestinal mucositis. Pathway analysis of the 12 most prominent proteins indicated that they could be assembled into a single interaction network with direct associations. The function associated with the highest number of these 12 proteins was cell-to-cell signaling and interaction. Pre-radiation proteomic profiles have the potential to classify cervical/endometrial cancer patients with high accuracy as to their susceptibility to gastrointestinal mucositis following radiation therapy. Further study of the network of 12 identified proteins is warranted with a larger patient sample to confirm that these proteins are predictive of gastrointestinal mucositis in this patient population.


The Tufts partnership for managed care education.
The authors describe the formation and the academic activities of the Tufts Managed Care Institute, a collaborative venture of Tufts University School of Medicine and Tufts Health Plan, an independent-practice-association (IPA)-model health maintenance organization (HMO). In 1994, the dean of the medical school and the CEO of the HMO recognized the need for collaboration to prepare students and practitioners for high-quality, cost-effective practice in a managed care environment. They established an advisory committee to oversee a six-month feasibility study to interview experts and opinion leaders and identify critical characteristics of the ideally prepared managed care practitioner. In 1995, with start-up funding from the HMO, the institute began its operations as a freestanding enterprise with board representation from the two sponsoring institutions. While many of the institute's programs have been developed for practicing physicians and other health care professionals, this article focuses on the academic activities. For medical students, the approach has been to blend managed care principles and practices into existing courses, problem-based learning cases, and clerkships, rather than creating separate managed care courses. For primary care residents, the institute has a grant to develop managed care curricula in conjunction with Tufts-affiliated residency training programs. Faculty development is accomplished through dedicated workshops and seminars, and through increased dialogue between traditional faculty and managed care professionals. In all of its programs and activities the institute has fostered greater contact and collaboration between colleagues from both sides of the health plan-academia "divide." Operationally, the institute structure, with dedicated full-time administrative staff, provides the singular focus necessary to establish managed care education as a top priority for the partnership. At the same time, sustaining this freestanding organization and infrastructure requires increased resources. Initial responses to the institute's programs and activities have been positive, both from the local Tufts community and from external parties. Yet the partnership must establish methods to evaluate the institute's long-term impact in its efforts to help practitioners succeed in a transforming landscape.


Joint effects of genetic variants in multiple loci on the risk of coronary artery disease in Chinese Han subjects.
The aim of the present study was to explore risk variants for coronary artery disease (CAD) and to evaluate their joint effects (quantified by genetic risk score; GRS) on the discrimination of CAD in a Chinese Han sample. An association analysis of 91 single nucleotide polymorphisms (SNPs) with CAD risk was undertaken in 1,007 CAD patients and 889 healthy controls. Two GRSs, counted GRS (cGRS) and weighted GRS (wGRS), were calculated using the significant SNPs, and their discriminant power for CAD was assessed using receiver-operating characteristic (ROC) curve analysis. Eight SNPs (rs11206510, rs10118757, rs2383206, rs501120, rs2075292, rs174547, rs173539, and rs255052) were nominally significantly associated with CAD (P<0.05), and 5 of them were newly reported. The GRSs derived from the 8 SNPs improved the discrimination of CAD compared to that using 4 conventional risk factors (P=0.002 for cGRS and P=0.009 for wGRS). After 10-fold cross-validation 100 times, the average areas under the curve were 0.668 (95% confidence interval [CI]: 0.667-0.669), 0.686 (95% CI: 0.685-0.687) and 0.690 (95% CI: 0.689-0.691) for models with conventional risk factors only, conventional risk factors plus cGRS, and conventional risk factors plus wGRS, respectively. A multigenic GRS, generated by combining multiple gene variants, can improve discrimination of CAD, thereby confirming the joint effects of these gene variants on CAD in this Chinese Han population.


Skin temperature reveals the intensity of acute stress.
Acute stress triggers peripheral vasoconstriction, causing a rapid, short-term drop in skin temperature in homeotherms. We tested, for the first time, whether this response has the potential to quantify stress, by exhibiting proportionality with stressor intensity. We used established behavioural and hormonal markers: activity level and corticosterone level, to validate a mild and more severe form of an acute restraint stressor in hens (Gallus gallus domesticus). We then used infrared thermography (IRT) to non-invasively collect continuous temperature measurements following exposure to these two intensities of acute handling stress. In the comb and wattle, two skin regions with a known thermoregulatory role, stressor intensity predicted the extent of initial skin cooling, and also the occurrence of a more delayed skin warming, providing two opportunities to quantify stress. With the present, cost-effective availability of IRT technology, this non-invasive and continuous method of stress assessment in unrestrained animals has the potential to become common practice in pure and applied research.


Effectiveness of Vortioxetine in Patients With Major Depressive Disorder in Real-World Clinical Practice: Results of the RELIEVE Study.
Randomized controlled clinical trials have shown vortioxetine to be efficacious and well tolerated for the treatment of major depressive disorder (MDD). The Real-Life Effectiveness of Vortioxetine in Depression (RELIEVE) study was undertaken to demonstrate the effectiveness and safety of vortioxetine for the treatment of MDD in routine clinical practice. RELIEVE was a 24-week, observational, prospective cohort study in outpatients with MDD initiating treatment with vortioxetine at their physician's discretion in routine care settings in Canada, France, Italy, and the USA (NCT03555136). The primary study outcome was patient functioning assessed by the Sheehan Disability Scale (SDS). Secondary outcomes included depression severity [9-item Patient Health Questionnaire (PHQ-9)], cognitive symptoms [5-item Perceived Deficits Questionnaire-Depression (PDQ-D-5)], and cognitive performance [Digit Symbol Substitution Test (DSST)]. Mixed models of repeated measures were used to assess change from baseline at week 24, adjusted for relevant confounders. A total of 737 patients were eligible for inclusion in the full analysis set. Most patients (73.7%) reported at least one comorbid medical condition, 56.0% had comorbid anxiety and 24.4% had comorbid generalized anxiety disorder. Improvement in least-squares (LS) mean SDS score from baseline to week 24 was 8.7 points. LS mean PHQ-9, PDQ-D-5 and DSST scores improved by 7.4, 4.6, and 6.2 points, respectively. Adverse events were observed in 21.2% of patients [most commonly, nausea (8.2% of patients)]. These results demonstrate the effectiveness and tolerability of vortioxetine for the treatment of MDD in a large and heterogeneous patient population representative of that encountered in routine clinical practice.


Functions of reminiscence and the psychological well-being of young-old and older adults over time.
Existing cross-sectional research demonstrates an association between reminiscence functions and well-being in later life. The results of this study replicate and extend previous findings in separate participant samples above and below 70 years of age. Findings suggest a link between reminiscence functions and psychological well-being, and indirectly between reminiscence and well-being 16 months thereafter. Invariance analyses reveal few differences in association between reminiscence and well-being when young-old (n = 196) and older adults (n = 215) are compared. These findings suggest a direct positive association between self-positive reminiscence functions (identity, death preparation, and problem-solving) and a direct negative association between self-negative functions (boredom reduction, bitterness revival, and intimacy maintenance) and psychological well-being (life satisfaction, depressive, and anxiety symptoms). In contrast, prosocial reminiscence functions (conversation, teach/inform others) appear to have an indirect association with well-being (i.e., via self-positive and self-negative functions). These findings are discussed relative to evolving theory and research linking cognition and health.


Effect of cadence on volume and myoelectric activity during agonist-antagonist paired sets (supersets) in the lower body.
The aim of this study was to investigate the effect of cadence on volume load (VLoad) and muscle activity during agonist -antagonist paired sets (APS) in the lower body. Twelve trained men (24.0 ± 3.3 years; 78.3 ± 9.7 kg; 1.77 ± 0.58 m) volunteered to participate in this study. After the 10 maximum repetition test for leg extension and seated leg curl, participants performed three experimental protocols: first protocol (traditional)-three sets of only leg extension (60 bpm); second protocol (fast cadence)-three sets of leg extension, with each set preceded by one set on the seated leg curl with fast cadence (90 bpm); third protocol (slow cadence)-similar to the second, but seated leg curl with slow cadence (40 bpm). The total number of repetitions, VLoad and the electromyography activity for the vastus lateralis, vastus medialis and rectus femoris muscles were recorded. The VLoad was higher during APS than the traditional method, but the cadence (fast or slow) of antagonist exercise did not influence VLoad. Muscle activity of vastus lateralis was higher during traditional protocol; on the other hand, rectus femoris showed higher activity on APS fast cadence protocol, indicating that APS has a different influence on quadriceps components.


Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function.
Coordinated cardiomyocyte growth, differentiation, and morphogenesis are essential for heart formation. We demonstrate that the bHLH transcription factors Hand1 and Hand2 play critical regulatory roles for left ventricle (LV) cardiomyocyte proliferation and morphogenesis. Using an LV-specific Cre allele (Hand1LV-Cre), we ablate Hand1-lineage cardiomyocytes, revealing that DTA-mediated cardiomyocyte death results in a hypoplastic LV by E10.5. Once Hand1-linage cells are removed from the LV, and Hand1 expression is switched off, embryonic hearts recover by E16.5. In contrast, conditional LV loss-of-function of both Hand1 and Hand2 results in aberrant trabeculation and thickened compact zone myocardium resulting from enhanced proliferation and a breakdown of compact zone/trabecular/ventricular septal identity. Surviving Hand1;Hand2 mutants display diminished cardiac function that is rescued by concurrent ablation of Hand-null cardiomyocytes. Collectively, we conclude that, within a mixed cardiomyocyte population, removal of defective myocardium and replacement with healthy endogenous cardiomyocytes may provide an effective strategy for cardiac repair.


The world of nursing on prime time television, 1950 to 1980.
This study reported the results of a content analysis of prime-time television portrayals of nurses and nursing over the past three decades with attention to scope of nursing practice, career orientation of nurses, nursing actions, and nurses' impact on patient welfare. The sample was 320 episodes from 28 series. The findings showed that nurses were depicted as working in acute care settings, entering nursing for altruistic reasons, predominantly acting as a resource to other health professionals, not using problem-solving and evaluation skills, deficient in administrative abilities, and remiss in providing physical comforting, engaging in expanded role activities, patient education and scholarly endeavors. Since the 1960s the trend in the quality of nurse portrayals has been downward. This has created a current crisis in communicating the world of nursing to the public via the most powerful form of mass communication, television.


Body fat distribution in childhood obesity: association with metabolic risk factors.
To evaluate the clinical significance of body fat distribution in childhood obesity, we investigated the associations of subcutaneous and intraabdominal (preperitoneal and visceral) fat, estimated by ultrasonography, with metabolic risk factors. Fifty-one obese (age 11.5+/- 2.6 years) and 33 non-obese (age 12.2+/- 2.7 years) children. Case control study. Ultrasonographic measurements of fat thickness [maximum and minimum preperitoneal fat thicknesses (Pmax, Pmin), maximum and minimum subcutaneous fat thicknesses (Smax, Smin), visceral fat thickness (V), triceps (Tr) and subscapular (Ss) skin fold thicknesses] were documented. Blood pressures, lipid profiles, fasting insulin levels, glucose/insulin ratio and HOMA IR (homeostasis model assessment for insulin resistance) were evaluated in both groups and these parameters were correlated with body fat distribution. In the obese group, fasting insulin level was correlated to Smin, Smax, and Pmin. HOMA, accordingly, was also correlated to Smin, Smax, and Pmin. Fasting insulin level and HOMA showed no correlation with either Pmax or visceral fat thickness. Abdominal subcutaneous fat thickness measurements were the best predictors of hyperinsulinemia (R2: 0.32). We did not observe a significant correlation between blood pressure, lipid parameters and body fat distribution in obese group. Abdominal subcutaneous fat thickness might be a better predictor of the risk for hyperinsulinemia in childhood obesity.


Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.
Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.


Unidirectional Sidechain Engineering to Construct Dual-Asymmetric Acceptors for 19.23 % Efficiency Organic Solar Cells with Low Energy Loss and Efficient Charge Transfer.
Achieving both high open-circuit voltage (Voc ) and short-circuit current density (Jsc ) to boost power-conversion efficiency (PCE) is a major challenge for organic solar cells (OSCs), wherein high energy loss (Eloss ) and inefficient charge transfer usually take place. Here, three new Y-series acceptors of mono-asymmetric asy-YC11 and dual-asymmetric bi-asy-YC9 and bi-asy-YC12 are developed. They share the same asymmetric D1 AD2 (D1 =thieno[3,2-b]thiophene and D2 =selenopheno[3,2-b]thiophene) fused-core but have different unidirectional sidechain on D1 side, allowing fine-tuned molecular properties, such as intermolecular interaction, packing pattern, and crystallinity. Among the binary blends, the PM6 : bi-asy-YC12 one has better morphology with appropriate phase separation and higher order packing than the PM6 : asy-YC9 and PM6 : bi-asy-YC11 ones. Therefore, the PM6 : bi-asy-YC12-based OSCs offer a higher PCE of 17.16 % with both high Voc and Jsc , due to the reduced Eloss and efficient charge transfer properties. Inspired by the high Voc and strong NIR-absorption, bi-asy-YC12 is introduced into efficient binary PM6 : L8-BO to construct ternary OSCs. Thanks to the broadened absorption, optimized morphology, and furtherly minimized Eloss , the PM6 : L8-BO : bi-asy-YC12-based OSCs achieve a champion PCE of 19.23 %, which is one of the highest efficiencies among these annealing-free devices. Our developed unidirectional sidechain engineering for constructing bi-asymmetric Y-series acceptors provides an approach to boost PCE of OSCs.


Paediatric eye injuries during a COVID-19 pandemic lockdown.
Eye injuries, both accidental and non-accidental, are a significant cause of long-term visual impairment in children. An understanding of when and how such injuries occur is key to development of adequate prevention strategies. To evaluate accidental and non-accidental eye injuries in children presenting to the major tertiary emergency department and outpatient ophthalmology clinic in Western Australia during the nationwide COVID-19 lockdown and to determine whether the frequency or nature of these injuries differed from pre-pandemic presentations. Retrospective review of the medical records of paediatric patients presenting to the emergency department and specialist ophthalmology clinic with an ocular injury and those presenting to the hospital Child Protection Unit with physical injuries during March-August 2020 and the same period in 2019. There was no significant difference in the total number of accidental eye injury presentations during the lockdown period despite a significant decrease in emergency department attendance overall. Closed-globe injuries were the most common accidental eye injury presentation during lockdown (70/110, 64%), followed by adnexal injuries (39/110, 35%) and open-globe injuries (1/110, 1%). In contrast, referrals to the hospital Child Protection Unit for suspicious injuries declined during lockdown. Although eye injury presentations have changed in other parts of the world since the start of the pandemic, during COVID-19 lockdown in Western Australia, accidental paediatric ocular and adnexal trauma sustained at home continues to be a significant cause for hospital attendance. Public education regarding in-home eye injury prevention must be ongoing.


Current issues in breast cytopathology.
This article explores 3 aspects of breast diagnosis that are currently under investigation and about which our thinking has recently undergone considerable reshaping. The trend toward more frequent evaluation of clinically subtle lesions has suggested that it might be necessary to understand thefine-needle aspiration (FNA) presentation of proliferative breast disease. Efforts to do so, as well as our suggestions for additional studies and their potential limitations open this discussion. Following this section, the increasingly useful method of intraoperative cytology for evaluation of resected breast masses is considered in detail. In the final section, optimization of nonoperative sampling by combination of mammography, ultrasonography, fine-needle aspiration, and core biopsy is discussed and illustrated.


Emphysema induced in vitro and in vivo in dogs by a purified elastase from homologous leukocytes.
The protease hypothesis of emphysema development evolved from systems using intratracheal instillation or aerosols of heterologous enzymes, such as papain or porcine pancreatic elastase, which bear no relation to the animal species treated. Although these enzymes did produce experimental emphysema, their exogenous origin and superphysiological dosages limit their use in definitive model systems. The observation that dog leukocyte homogenates could induce canine emphysema led us to purify the causative agent from canine neutrophils. This report establishes that a single elastolytic enzyme from dog neutrophils is responsible for inducing experimental emphysema in the dog. Two purification methods were employed. The first used solvents of increasing ionic strength in a sequential extraction of acetone powders of purified dog neutrophils. The ability to initiate emphysema-like lesions was tested in every fraction of the purification and was localized in the extract with the highest true elastolytic activity. The second purification involved neutrophil intracytoplasmic organelle fractionation and established that only extracts of the lysosomal granules were capable of emphysema induction. Finally, the enzyme was purified to homogeneity from the granules using affinity chromatography and was shown to be a true elastase. Emphysema development was quantitated using mean linear intercept and was shown to be dependent on elastase concentration. There does not appear to be any other single enzyme in the canine neutrophil capable of inducing experimental emphysema.


A 19-year-old man with leucocyte adhesion deficiency. In vitro and in vivo studies of leucocyte function.
We describe a male patient with leucocyte adhesion molecule deficiency (LAD) of moderate phenotype. Although diagnosis was made only 2 years before his death, the patient survived until 19 years of age. This enabled us to perform a number of novel investigation, both in vivo and in vitro, relating to his leucocyte biology. Monocytes cultured in vitro matured into morphologically normal, phagocytically capable macrophages, which were able to recognize aged 'apoptotic' neutrophils. By injection of radiolabelled autologous neutrophils we demonstrated a prolonged neutrophil half-life, but normal margination, de-margination on exercise, and splenic pooling. Neutrophil adherence in vitro to vascular endothelium was normal. Histological examination of the patient's lungs at post-mortem showed intravascular aggregation of polymorphonuclear leucocytes but a paucity of cells in the interstitium and alveolar spaces. These findings indicate that the peripheral blood leucocytosis commonly observed in these patients may be due to prolonged intravascular neutrophil survival, and suggest that CD11/18 molecules have an important role in facilitating neutrophil emigration from blood vessels at sites of inflammation.


CBCT with specification of imaging dose and CNR by anatomical volume of interest.
A novel method has been developed for volume of interest (VOI) cone-beam CT (CBCT) imaging using a 2.35 MV/Carbon target linac imaging beam line combined with dynamic multileaf collimator sequences. The authors demonstrate the concept of acquisition of multiple, separate imaging volumes, where volumes can be either completely separated or nested, and are associated with predetermined imaging dose and contrast-to-noise ratio (CNR) characteristics. Two individual MLC sequences were established in the planning system (Eclipse, Varian Medical) to collimate the beam according to a defined inner VOI (e.g., containing a target volume under image guidance) and an outer VOI (e.g., including surrounding landmarks or organs-at-risk). MLC sequences were interleaved as a function of gantry angle to produce a reconstructed CBCT image with nested VOIs. By controlling the ratio of inner-to-outer ratio of MLC segments (and thus Monitor Units) during acquisition, the relative dose and CNR in the two volumes can be controlled. Inner-to-outer ratios of 2:1 to 6:1 were examined. The concept was explored using an anatomical head phantom to assess image quality. A geometric phantom was used to quantify absolute dose and CNR values for the various sequences. The authors found that the dose in the outer VOI decreased by a functional relationship dependent on the inner-to-outer sequence ratio, while the CNR varied by the square root of dose, as expected. In this study the authors demonstrate flexibility in VOI CBCT by tailoring the imaging dose and CNR distribution in separate volumes within the patient anatomy. This would allow for high quality imaging of a target volume for alignment purposes, with simultaneous low dose imaging of the surrounding anatomy (e.g., for coregistration).


Diabetes and hyperlipidemia induce dysfunction of VSMCs: contribution of the metabolic inflammation/miRNA pathway.
Vascular endothelial cell injury is considered to be the major factor inducing vascular complications in metabolic diseases and plays an important role in other organ damage. With diabetic and hyperlipidemic rats and cultured VSMCs, the present study was aimed at investigating whether the early damage of VSMCs during metabolic diseases plays a critical role in vascular dysfunction and the underlying mechanisms and would be a promising treatment target. With diabetic and hyperlipidemic rats and cultured VSMCs, the changes and relationships of vascular relaxation and contractile function to the vital organ damage and the underlying mechanisms were investigated; meanwhile, the protective and preventive effects of lowering blood lipid and glucose and inhibition of diabetes and hyperlipidemia-induced vascular hyperreactivity were observed. Diabetic and hyperlipidemic rats presented hyperreactivity in vascular contractile response in the early stages. Hyperglycemia and hyperlipidemia directly affected the contractile function of VSMCs. Early application of fasudil, a specific antagonist of Rho kinase, significantly alleviated diabetes and hyperlipidemia-induced organ damage by inhibiting vascular hyperreactivity. Diabetes and hyperlipidemia-induced inflammatory response could upregulate the expression of connexins and Rho kinase by selective downregulation of the expression of miR-10a, miR-139b, miR-206, and miR-222. These findings suggest that hyperglucose and lipid may directly impair VSMCs and induce vascular hyperreactivity in the early stages. Metabolic inflammation-induced changes in the miRNA-connexin/Rho kinase regulatory pathway are the main mechanism for vascular hyperreactivity and organ damage. Measures inhibiting vascular hyperreactivity are promising for the prevention of organ damage induced by metabolic diseases.


Budesonide-related adrenal insufficiency.
Iatrogenic adrenal insufficiency is a potential harmful side effect of treatment with corticosteroids. It manifests itself when an insufficient cortisol response to biological stress leads to an Addisonian crisis: a life-threatening situation. We describe a case of a patient who developed an Addisonian crisis after inappropriate discontinuation of budesonide (a topical steroid used in Crohn's disease) treatment. Iatrogenic adrenal insufficiency due to budesonide use has been rarely reported. Prescribers should be aware of the resulting risk for an Addisonian crisis.


Leukocyte Telomere Length Shortening Implies Plaque Instability and Major Adverse Cardiovascular Events in Patients With Angiographically Intermediate Lesions.
Telomere shortening, an indicator of aging, is associated with age-related diseases. This study aims to investigate the association between leukocyte telomere length (LTL) and thin-capped fibroatheromata (TCFA) and the impact of using LTL cutoff to determine the incidence of major adverse cardiovascular events (MACEs) in patients with angiographically intermediate coronary lesions. This was a signal-center retrospective study focusing on patients who underwent coronary angiography and optical coherence tomography (OCT). The degree of coronary stenosis was assessed by angiography. The presence of TCFA was determined by OCT imaging. A total of 156 patients with angiographically intermediate coronary lesions were enrolled. Leukocyte telomere lengths were significantly shorter in the TCFA group compared with non-TCFA group [11.95 (10.56, 15.21) kb vs. 13.81 (12.06, 16.11) kb, p = 0.003]. The short-LTL group and long-LTL group were divided according to the optimal cut-off value which was determined by the receiver operating characteristic (ROC) curve analysis. Logistic regression model revealed that short-LTL was independently associated with TCFA incidence (odds ratio [OR] 4.387, 95% CI: 1.902-10.120, p = 0.001) after adjusting for confounding factors. Over a 24-months follow-up, the MACE incidence among patients with short-LTL was significantly higher than those in the long-LTL group (12.5 vs. 2.0%, p = 0.006 by log-rank test). Multivariable cox regression analysis indicated that short-LTL (hazard ratio [HR] 9.716, 95% CI: 1.995-47.319, p = 0.005) was an independent prognostic factor of MACE incidence in angiographically intermediate coronary lesions patients. Short-LTL was independently associated with the incidence of TCFA and may serve as a prognostic factor for MACE risk on top of conventional risk factors.


General measures of cognition for the preschool child.
Preschool-age children who are experiencing delays in physical, cognitive, communication, social, emotional, or adaptive development are often referred for a comprehensive assessment to make diagnostic determinations and to help develop appropriate interventions. Typically cognitive assessment has a key role in a comprehensive evaluation of a young child. In this article, five individually administered tests of cognitive ability, normed for the preschool-age child, are reviewed. These specific tests include the Bayley Scales of Infant Development, 2nd edition, the Kaufman Assessment Battery for Children, 2nd edition, the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, the Stanford-Binet Intelligence Scale, 5th edition, and the Differential Abilities Scales. The following is provided for these cognitive instruments: a description of the test procedures, information on scoring systems, highlights of the technical qualities, and a summary of the general meaning of test results. The article concludes with strengths and limitations of the instruments.


Problems paying medical bills and mental health symptoms post-Affordable Care Act.
Healthcare affordability is a worry for many Americans. We examine whether the relationship between having problems paying medical bills and mental health problems changed as the Affordable Care Act (ACA) was implemented, which increased health insurance coverage. Data from the 2013-2016 Health Reform Monitoring Survey, a survey of Americans aged 18-64, were used. Using zero-inflated negative binomial regression, adjusted for predisposing, enabling, and need factors, we examined differences in days of mental health symptoms by problems paying medical bills (n = 85,430). From 2013 to 2016, the rates of uninsured and problems paying medical bills decreased from 15.1% to 9.0% and 22.0% to 18.6%, respectively. Having one or more days of mental health symptoms increased from 39.3% to 42.9%. Individuals who reported problems paying medical bills had more days of mental health symptoms (Beta = 0.133, p < 0.001) than those who did not have this problem. Insurance was not significantly associated with days of mental health symptoms. Over the 4-year period, there were not significant differences in days of mental health symptoms by problems paying medical bills or insurance status. Despite improvements in coverage, the relationship between problems paying medical bills and mental health symptoms was not modified.


Lipase applications in oil hydrolysis with a case study on castor oil: a review.
Lipase (triacylglycerol acylhydrolase) is a unique enzyme which can catalyze various types of reactions such as hydrolysis, esterification, alcoholysis etc. In particular, hydrolysis of vegetable oil with lipase as a catalyst is widely studied. Free lipase, lipase immobilized on suitable support, lipase encapsulated in a reverse micelle and lipase immobilized on a suitable membrane to be used in membrane reactor are the most common ways of employing lipase in oil hydrolysis. Castor oil is a unique vegetable oil as it contains high amounts (90%) of a hydroxy monounsaturated fatty acid named ricinoleic acid. This industrially important acid can be obtained by hydrolysis of castor oil. Different conventional hydrolysis processes have certain disadvantages which can be avoided by a lipase-catalyzed process. The degree of hydrolysis varies widely for different lipases depending on the operating range of process variables such as temperature, pH and enzyme loading. Immobilization of lipase on a suitable support can enhance hydrolysis by suppressing thermal inactivation and estolide formation. The presence of metal ions also affects lipase-catalyzed hydrolysis of castor oil. Even a particular ion has different effects on the activity of different lipases. Hydrophobic organic solvents perform better than hydrophilic solvents during the reaction. Sonication considerably increases hydrolysis in case of lipolase. The effects of additives on the same lipase vary with their types. Nonionic surfactants enhance hydrolysis whereas cationic and anionic surfactants decrease it. A single variable optimization method is used to obtain optimum conditions. In order to eliminate its disadvantages, a statistical optimization method is used in recent studies. Statistical optimization shows that interactions between any two of the following pH, enzyme concentration and buffer concentration become significant in presence of a nonionic surfactant named Span 80.


On the late prognosis of type A virus hepatitis.
5.2% healings by second intention must be added to the 91.4% healings by first intention. The proportion of patients (1.1%) who could not be followed up for various reasons is but small. In view of the findings of this epidemiologically founded study, it seems justified to conclude that the long-term prognosis of acute type A virus hepatitis may be considered to be favourable since healing occurred in 96.6%.


Cloning of the xynB gene from Dictyoglomus thermophilum Rt46B.1 and action of the gene product on kraft pulp.
A two-step PCR protocol was used to identify and sequence a family 11 xylanase gene from Dictyoglomus thermophilum Rt46B.1. Family 11 xylanase consensus fragments (GXCFs) were amplified from Rt46B.1 genomic DNA by using different sets of consensus PCR primers that exhibited broad specificity for conserved motifs within fungal and/or bacterial family 11 xylanase genes. On the basis of the sequences of a representative sample of the GXCFs a single family 11 xylanase gene (xynB) was identified. The entire gene sequence was obtained in the second step by using genomic walking PCR to amplify Rt46B.1 genomic DNA fragments upstream and downstream of the xynB GXCF region. The putative XynB peptide (M(r), 39,800) encoded by the Rt46B.1 xynB open reading frame was a multidomain enzyme comprising an N-terminal catalytic domain (M(r), 22,000) and a possible C-terminal substrate-binding domain (M(r), 13,000) that were separated by a short serine-glycine-rich 23-amino-acid linker peptide. Seven xylanases which differed at their N and C termini were produced from different xynB expression plasmids. All seven xylanases exhibited optimum activity at pH 6.5. However, the temperature optima of the XynB xylanases varied from 70 to 85 degrees C. Pretreatment of Pinus radiata and eucalypt kraft-oxygen pulps with XynB resulted in moderate xylan solubilization and a substantial improvement in the bleachability of these pulps.


Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance.
The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer.


Effect of an anti-CD54 (ICAM-1) monoclonal antibody (UV3) on the growth of human uveal melanoma cells transplanted heterotopically and orthotopically in SCID mice.
We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab')2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab')2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma.


Diversity and arsenic-tolerance potential of bacterial communities from soil and sediments along a gold tailing contamination gradient.
Gold tailings often release arsenic (As) contaminants into the surrounding environment. Microorganisms play an important role in the As cycle, whereas the effects of As on bacterial communities remain unclear. To reveal the effects of As on the diversity of bacterial communities and their As-tolerance potential, farmland soil and river sediment samples were collected at various distances from tailings in the Dandong area of northeastern China. The bacterial communities were analyzed using high-throughput sequencing of 16S rRNA genes. The membrane transport proteins ArsB and (or) ACR3 pump As(III) out of the cell to resist As toxicity. We studied the abundance and phylogeny of ArsB and ACR3 using PCR-based clone libraries and quantitative PCR. The bacterial community was divided into 10 phyla and 59 genera. The transformation from As(V) to As(III) was predominant, which was coupled with denitrification. Both ArsB and ACR3 likely evolved from different orders of Proteobacteria. The arsB gene seems to be more stable in bestowing bacteria with the capability to respond to the As concentration. Moreover, As with iron, manganese, and total organic carbon also influenced the clustering relationships of samples and bacterial distribution.


Duration of suppression of adrenal steroids after glucocorticoid administration.
Hydrocortisone has long been the treatment of choice for congenital adrenal hyperplasia (CAH). However, treatment with this medication remains problematic. Patients with 21-hydroxylase deficiency CAH have significant diurnal variation in the secretion of 17-hydroxyprogesterone (17OHP). When considering treatment strategies, this variation must be considered along with the pharmacokinetic and pharmacodynamic properties of exogenous glucocorticoids. Orally administered hydrocortisone is highly bioavailable, but it has a short time to maximum concentration (T(max)) and half life (T(1/2)). While prednisone has a somewhat longer T(max) and T(1/2), they remain relatively short. There have been several studies of the pharmacodynamics of hydrocortisone. We present data indicating that the maximum effect of hydrocortisone in CAH patients is seen 3 hours after a morning dose. After an evening dose, suppression of adrenal hormones continues until approximately 0500 the next day. In both situations, however, there is a large degree of intersubject variability. These data are consistent with earlier published studies. Use of alternate specimen types, possibly in conjunction with delayed release hydrocortisone preparations under development, may allow the practitioner to design a medication regimen that provides improved control of androgen secretion. Whatever dosing strategy is used, clinical judgment is required to ensure the best outcome.


High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway.
Activation of endothelial adenosine monophosphate-activated protein kinase (AMPK) contributes to increase nitric oxide (NO) availability. The aim of this study was to assess if high-fat diet (HFD)-induced endothelial dysfunction is linked to AMPK deregulation. Twelve-week-old Sprague Dawley male rats were assigned either to control (10 kcal % from fat) or to HFD (45 kcal % from fat) for 8 wk. HFD rats segregated in obesity-prone (OP) or obesity-resistant (OR) rats according to body weight. HFD triggered an impaired glucose management together with impaired endothelium-dependent relaxation, reduced endothelial AMPK activity and lower NO availability in aortic rings of OP and OR cohorts. Relaxation evoked by AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) was reduced in both OP and OR rings, which exhibited lower p-AMPKα-Thr(172) /AMPKα ratios that negatively correlated with plasma non-esterified fatty acids (NEFA) and triglycerides (TG). Inhibition of PI3K (wortmannin, 10(-7) M) or Akt (triciribine, 10(-5) M) reduced relaxation to AICAR only in the control group (p < 0.001). Akt (p-Akt-Ser(473) ) and eNOS phosphorylation (p-eNOS-Ser(1177) ) were significantly reduced in OP and OR (p < 0.01). Endothelial dysfunction caused by HFD is related to a dysfunctional endothelial AMPK-PI3K-Akt-eNOS pathway correlating with the increase of plasma NEFA, TG, and an impaired glucose management.


Analysis of prefitting versus postfitting hearing aid orientation using the Glasgow Hearing Aid Benefit Profile (GHABP).
Results of this study demonstrate the advantages of both pre- and postfitting hearing aid orientation (HAO) sessions. This study demonstrated that HAO counseling is helpful in expediting hearing aid benefit and satisfaction through the education of our clients and that this benefit and satisfaction is age dependent as measured by the Glasgow Hearing Aid Benefit Profile (GHABP) (Gatehouse, 1997). Patients with greater initial disability, as identified by item 1 of the GHABP, receive significant benefit from prefitting and/or postfitting counseling as compared to patients receiving no counseling. Implications of these findings are discussed.


[Efficacy of gamma-irradiated adipose-derived stem cells for treatment of thin endometrium in rats].
Transplantation of adipose-derived stem cells (ADSCs) is associated with potential risks of late complications including tumorigenesis due to the active proliferation of the cells. We aimed to test the effect of transplantation of ADSCs with suppressed proliferation by gamma irradiation in the treatment of thin endometrium in rats. ADSCs were isolated from female SD rats and identified by detecting the surface antigens with flow cytometry. After exposure to gamma irradiation at 0, 5 Gy and 10 Gy, the cells were examined for changes in colony-forming ability. Twenty-four female rats with chemically induced thin endometrium were randomized into 4 equal groups and at 6-8 h after modeling, the rats received intrauterine injection of non-irradiated ADSCs (group I), 5 Gy irradiated ADSCs (group II), 10 Gy irradiated ADSCs (group III), or PBS only (group IV). Endometrial pathology was analyzed with HE staining in these rats in the third estrus phase following the cell transplantation. The ADSCs showed a complete loss of proliferative capacity after exposure to 10 Gy irradiation. After the cell transplantation, the endometrium thickness was thicker in group I and II than in group IV (P<0.01), but there was no significant difference between groups III and IV. Gamma irradiation impairs the proliferative capacity of ADSCs in vitro. Exposure to 10 Gy irradiation causes a total loss of proliferation capacity of the ADSCs, which have no therapeutic potential; 5 Gy irradiation causes partial loss of proliferation capacity of the cells, which still retain the activity to promote endometrial cell regeneration.


[Correlation of alpha fetoprotein with the prognosis of hepatocellular carcinoma after hepatectomy in an ethnic Chinese population].
To explore the correlation between alpha fetoprotein (AFP) and the prognosis of hepatocellular carcinoma after hepatectomy in an ethnic Chinese population. This study retrospectively analyzed the surgical outcomes of hepatocellular carcinoma (HCC) in 779 patients undergoing hepatic resection between June 1999 and March 2010 at our hospital. The postoperative prognostic factors were assessed by univariate Kaplan-Meier analysis and a multivariate Cox proportional hazard model. The cut-off value of AFP was 18.98 µg/L by receiver operating characteristic (ROC) curve statistics and the sensitivity and specificity rates were 54.6% and 82.0% respectively. The overall survival (OS) rate of AFP negative group (AFP < 20 µg/L) for 1, 3 and 5-year was 94.4%, 77.3% and 58.9% while the OS rate of AFP positive group (AFP ≥ 20 µg/L) for 1, 3 and 5-year 90.6%, 64.5% and 49.6%. According to univariate analysis, better prognosis for OS was associated with asymptomatic presentation, no ascites, small tumor, single lesion, serological AFP negativity, serological alkaline phosphatase (ALP) negativity, high-grade histological differentiation, no carcinoma cell embolus, no/mild cirrhosis, Child-Pugh class A, no transfusion, no regional lymph node metastasis, no major vascular invasion, no direct invasion of adjacent organs or with perforation of visceral peritoneum. In multivariate analysis, asymptomatic presentation, young age, single lesion, Alpha-Fetoprotein (AFP) negative expression, serological alkaline phosphatase (ALP) negative expression, Child-Pugh class A, no carcinoma cell embolus, serological no regional lymph node metastasis, no major vascular invasion, no direct invasion of adjacent organs, no perforation of visceral peritoneum and non-transfusion were independent factors for longer OS. Then all patients were classified into different groups by various OS time of 1, 2, 3, 5-year respectively. The statistical results showed that patients with a low expression of serum AFP had better prognosis. Lower serum level of AFP indicates better prognosis while higher AFP level is directly correlated with more aggressive biological tumor activities, poor background of liver and poor prognosis.


Suggested new breakpoints of anti-MERS-CoV antibody ELISA titers: performance analysis of serologic tests.
To provide optimal cut-off values of anti-Middle East respiratory syndrome coronavirus (MERS-CoV) serologic tests, we evaluated performance of ELISA IgG, ELISA IgA, IFA IgM, and IFA IgG using 138 serum samples of 49 MERS-CoV-infected patients and 219 serum samples of 219 rRT-PCR-negative MERS-CoV-exposed healthcare personnel and patients. The performance analysis was conducted for two different purposes: (1) prediction of neutralization activity in MERS-CoV-infected patients, and (2) epidemiologic surveillance of MERS-CoV infections among MERS-CoV-exposed individuals. To evaluate performance according to serum collection time, we used 'days post onset of illness (dpoi)' and 'days post exposure (dpex)' assessing neutralization activity and infection diagnosis, respectively. Performance of serologic tests improved with delayed sampling time, being maximized after a seroconversion period. In predicting neutralization activity, ELISA IgG tests showed optimal performance using sera collected after 21 dpoi at cut-off values of OD ratio 0.4 (sensitivity 100% and specificity 100%), and ELISA IgA showed optimal performance using sera collected after 14 dpoi at cut-off value of OD ratio 0.2 (sensitivity 85.2% and specificity 100%). In diagnosis of MERS-CoV infection, ELISA IgG exhibited optimal performance using sera collected after 28 dpex, at a cut-off value of OD ratio 0.2 (sensitivity 97.3% and specificity 92.9%). These new breakpoints are markedly lower than previously suggested values (ELISA IgG OD ratio 1.1, sensitivity 34.8% and specificity 100% in the present data set), and the performance data help serologic tests to be practically used in the field of MERS management.


Clogging in constricted suspension flows.
The flow of a charged-stabilized suspension through a single constricted channel is studied experimentally by tracking the particles individually. Surprisingly, the behavior is found to be qualitatively similar to that of inertial dry granular systems: For small values of the neck-to-particle size ratio (D/d<3), clogs form randomly as arches of the particle span the constriction. The statistics of the clogging events are Poissonian as reported for granular systems and agree for moderate particle volume fraction (ϕ≈20%) with a simple stochastic model for the number of particles at the neck. For larger neck sizes (D/d>3), even at the largest ϕ(≈60%) achievable in the experiments, an uninterrupted particle flow is observed, which resembles that of an hourglass. This particularly small value of D/d(≃3) at the transition to a practically uninterrupted flow is attributed to the low effective friction between the particles, achieved by the particle's functionalization and lubrication.


Digital subtraction bowel cleansing for CT colonography using morphological and linear filtration methods.
We describe a method to perform postacquisition processing of computed tomography colonography (virtual colonoscopy) datasets that results in electronic removal of opacified, ingested bowel contents while reconstructing natural appearing boundaries of colon lumen and thereby permitting three-dimensional visual analyses of the resulting colon models.


Using chemical reaction network theory to discard a kinetic mechanism hypothesis.
Feinberg's chemical reaction network theory (CRNT) connects the structure of a biochemical reaction network to qualitative properties of the corresponding system of ordinary differential equations. No information about parameter values is needed. As such, it seems to be well suited for application in systems biology, where parameter uncertainty is predominant. However, its application in this area is rare. To demonstrate the potential benefits from its application, different reaction networks representing a single layer of the well-studied mitogen-activated protein kinase (MAPK) cascade are analysed. Recent results from Markevich et al. (2004) show that, unexpectedly, multilayered protein kinase cascades can exhibit multistationarity, even on a single cascade level. Using CRNT, we show that their assumption of a distributive mechanism for double phosphorylation and dephosphorylation is crucial for multistationarity on the single cascade level.


A hybrid method of recurrent neural network and graph neural network for next-period prescription prediction.
Electronic health records (EHRs) have been widely used to help physicians to make decisions by predicting medical events such as diseases, prescriptions, outcomes, and so on. How to represent patient longitudinal medical data is the key to making these predictions. Recurrent neural network (RNN) is a popular model for patient longitudinal medical data representation from the view of patient status sequences, but it cannot represent complex interactions among different types of medical information, i.e., temporal medical event graphs, which can be represented by graph neural network (GNN). In this paper, we propose a hybrid method of RNN and GNN, called RGNN, for next-period prescription prediction from two views, where RNN is used to represent patient status sequences, and GNN is used to represent temporal medical event graphs. Experiments conducted on the public MIMIC-III ICU data show that the proposed method is effective for next-period prescription prediction, and RNN and GNN are mutually complementary.


Evolutionary conservation of zebrafish linkage group 14 with frequently deleted regions of human chromosome 5 in myeloid malignancies.
Recurring interstitial loss of all or part of the long arm of chromosome 5, del(5q), is a hallmark of myelodysplastic syndrome and acute myeloid leukemia. Although the genes affected by these changes have not been identified, two critically deleted regions (CDRs) are well established. We have identified 76 zebrafish cDNAs orthologous to genes located in these 5q CDRs. Radiation hybrid mapping revealed that 33 of the 76 zebrafish orthologs are clustered in a genomic region on linkage group 14 (LG14). Fifteen others are located on LG21, and two on LG10. Although there are large blocks of conserved syntenies, the gene order between human and zebrafish is extensively inverted and transposed. Thus, intrachromosomal rearrangements and inversions appear to have occurred more frequently than translocations during evolution from a common chordate ancestor. Interestingly, of the 33 orthologs located on LG14, three have duplicates on LG21, suggesting that the duplication event occurred early in the evolution of teleosts. Murine orthologs of human 5q CDR genes are distributed among three chromosomes, 18, 11, and 13. The order of genes within the three syntenic mouse chromosomes appears to be more colinear with the human order, suggesting that translocations occurred more frequently than inversions during mammalian evolution. Our comparative map should enhance understanding of the evolution of the del(5q) chromosomal region. Mutant fish harboring deletions affecting the 5q CDR syntenic region may provide useful animal models for investigating the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia.


Cellular Senescence and Iron Dyshomeostasis in Alzheimer's Disease.
Iron dyshomeostasis is a feature of Alzheimer's disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.


Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion.
The present renal hemodynamic study tested the hypothesis that CD38 and superoxide anion (O2(·-)) participate in the vasoconstriction produced by activation of thromboxane prostanoid (TP) receptors in the mouse kidney. CD38 is the major mammalian ADP-ribosyl cyclase contributing to vasomotor tone through the generation of cADP-ribose, a second messenger that activates ryanodine receptors to release Ca(2+) from the sarcoplasmic reticulum in vascular smooth muscle cells. We evaluated whether the stable thromboxane mimetic U-46619 causes less pronounced renal vasoconstriction in CD38-deficient mice and the involvement of O2(·-) in U-46619-induced renal vasoconstriction. Our results indicate that U-46619 activation of TP receptors causes renal vasoconstriction in part by activating cADP-ribose signaling in renal resistance arterioles. Based on maximal renal blood flow and renal vascular resistance responses to bolus injections of U-46619, CD38 contributes 30-40% of the TP receptor-induced vasoconstriction. We also found that the antioxidant SOD mimetic tempol attenuated the magnitude of vasoconstriction by U-46619 in both groups of mice, suggesting mediation by O2(·-). The degree of tempol blockage of U-46619-induced renal vasoconstriction was greater in wild-type mice, attenuating renal vasoconstriction by 40% compared with 30% in CD38-null mice. In other experiments, U-46619 rapidly stimulated O2(·-) production (dihydroethidium fluorescence) in isolated mouse afferent arterioles, an effect abolished by tempol. These observations provide the first in vivo demonstration of CD38 and O2(·-) involvement in the vasoconstrictor effects of TP receptor activation in the kidney and in vitro evidence for TP receptor stimulation of O2(·-) production by the afferent arteriole.


Study on biofilm formation in burn wound infection in a pediatric hospital in Chennai, India.
Infection is one of the major causes of death in pediatric burns in India. This work was conducted in an exclusive Children's Hospital (KKCTH) with a total of 220 beds, of which ten beds in the burn unit and two isolation beds in the 28-bed PICU are for burns patients (more than 20% TBSA burns) with sepsis. In this study, 30 burn wound swab isolates obtained from 14 pediatric burns patients (admitted to the burns ward and transferred to PICU) from November 2013 to March 2014 were investigated. Cultures were done on the first day for all patients and empirical antibiotic administration was started for those with septic burns (14 in total) with piperacillin-tazobactam and vancomycin. Antibiotics were changed according to antibiotic sensitivity reports. Cultures were repeated for culture positive cases on the fifth day. Further antibiotic treatment was based on this culture report. When the general condition of the patient did not respond to highlevel antibiotics, biofilm formation was suspected and evaluated as the possible cause of antibiotic resistance. For these patients, an enhanced method of wound debridement and albumin transfusions were used to improve their general condition. Microbial identification and antimicrobial sensitivity testing was done for all 30 isolates. The predominant bacteria were Pseudomonas aeruginosa, Acinetobacter and Staphylococcus aureus. Most of the Acinetobacter and Staphylococcus aureus showed multidrug resistance. Biofilm formation was studied using the Tissue Culture Plate (TCP) method for all bacterial isolates, and results showed that most of the MDR isolates formed biofilm.


Justice sensitivity is undergirded by separate heritable motivations to be morally principled and opportunistic.
Injustice typically involves some people benefitting at the expense of others. An opportunist might then be selectively motivated to amend only the injustice that is harmful to them, while someone more principled would respond consistently regardless of whether they stand to gain or lose. Here, we disentangle such principled and opportunistic motives towards injustice. With a sample of 312 monozygotic- and 298 dizygotic twin pairs (N = 1220), we measured people's propensity to perceive injustice as victims, observers, beneficiaries, and perpetrators of injustice, using the Justice Sensitivity scale. With a biometric approach to factor analysis, that provides increased stringency in inferring latent psychological traits, we find evidence for two substantially heritable factors explaining correlations between Justice Sensitivity facets. We interpret these factors as principled justice sensitivity (h2 = 0.45) leading to increased sensitivity to injustices of all categories, and opportunistic justice sensitivity (h2 = 0.69) associated with increased sensitivity to being a victim and a decreased propensity to see oneself as a perpetrator. These novel latent constructs share genetic substrate with psychological characteristics that sustain broad coordination strategies that capture the dynamic tension between honest cooperation versus dominance and defection, namely altruism, interpersonal trust, agreeableness, Social Dominance Orientation and opposition to immigration and foreign aid.


Clinical pharmacology of NSAIDs.
All nonsteroidal anti inflammatory drugs (NSAIDs) are characterized by a high degree of protein binding and small volumes of distribution. Differences in clearance account for the variability in half-life among these drugs. The majority are metabolized by the liver through a variety of pathways. These drugs are subject to drug interactions of several mechanisms, including protein-binding-displacement interactions, induction or inhibition of hepatic drug metabolism, and competition for active renal tubular secretion with other organic acids. NSAIDs are also subject to special pharmacokinetic considerations about which a great deal has been learned recently. These include data demonstrating that assessment of disposition of these drugs using only total drug concentrations can be misleading and that one must instead assess the disposition of unbound, pharmacologically active drug. Second, it appears that only one enantiomer of the propionic acid NSAIDs is active; studies of the pharmacokinetics of this class of NSAID should include assessment of the active stereoisomer. Finally, the propionic acid NSAIDs are metabolized to acyl-glucuronide conjugates, which are unstable and can cleave back to the parent drug. This feature allows the paradox of a drug that is metabolized by the liver being able to accumulate in patients who have renal insufficiency. Because of these newer pharmacokinetic considerations, much of the old data concerning the clinical pharmacology of NSAIDs are obsolete. More precise new information is needed in this area.


Correcting spherical aberrations in confocal light sheet microscopy: a theoretical study.
In the last years, fluorescence light sheet microscopy has attracted an increasing interest among the microscopy community. One of the most promising applications of this technique is the reconstruction of macroscopic biological specimens with microscopic resolution, without physical sectioning. To this aim, light sheet microscopy is combined with clearing protocols based on refractive index matching, which render the tissue transparent. However, these protocols lead to a huge drop in the fluorescence signal, limiting their practical applicability. The reduction of signal to background ratio is commonly ascribed to chemical degradation of the fluorophores by the organic solvents used for clearing. This view however completely neglects another important factor of contrast loss, i.e., optical aberrations. In fact, commercially available objectives suitable for light sheet microscopy are not designed for the refractive index of the clearing solutions, and this mismatch introduces severe spherical aberration. Here we simulated the aberrated point spread function (PSF) of a light sheet microscope with confocal slit detection. We investigated the variation of the PSF as a function of objective numerical aperture (NA) and of imaging depth inside the clearing solution. We also explored the possibility of correcting such spherical aberration by introducing extra optical devices in the detection path. By correcting up to the second order spherical aberration, a quasi-diffraction-limited regime can be recovered, and image quality is restored.


Clindamycin and quinolone therapy for Bacillus anthracis Sterne infection in 60Co-gamma-photon-irradiated and sham-irradiated mice.
Sublethal ionizing doses of radiation increase the susceptibility of mice to Bacillus anthracis Sterne infection. In this study, we investigated the efficacy of clindamycin in 60Co-gamma-photon-irradiated and sham-irradiated mice after intratracheal challenge with B. anthracis Sterne spores. Clindamycin has in vitro activity against B. anthracis and inhibits the production of toxin from other species, although no direct evidence exists that production of B. anthracis toxin is inhibited. Ten-week-old B6D2F1/J female mice were either sham-irradiated or given a sublethal 7 Gy dose of 60Co-gamma-photon radiation 4 days prior to an intratracheal challenge with toxigenic B. anthracis Sterne spores. Mice were treated twice daily with 200 mg/kg clindamycin (subcutaneous or oral), 100 mg/kg moxifloxacin (oral), 50 mg/kg ciprofloxacin (subcutaneous) or a combination therapy (clindamycin + ciprofloxacin). Bacteria were isolated and identified from lung, liver and heart blood at five timed intervals after irradiation. Survival was recorded twice daily following intratracheal challenge. The use of clindamycin increased survival in gamma-irradiated and sham-irradiated animals challenged with B. anthracis Sterne in comparison with control mice (P < 0.001). Ciprofloxacin-treated animals had higher survival compared with clindamycin-treated animals in two experiments, and less survival in a third experiment, although differences were not statistically significant. Moxifloxacin was just as effective as clindamycin. Combination therapy did not improve survival of sham-irradiated animals and significantly decreased survival among gamma-irradiated animals (P = 0.01) in comparison with clindamycin-treated animals. B. anthracis Sterne was isolated from lung, liver and heart blood, irrespective of the antimicrobial treatment. Treatment with clindamycin, ciprofloxacin or moxifloxacin increased survival in sham-irradiated and gamma-irradiated animals challenged intratracheally with B. anthracis Sterne spores. However, the combination of clindamycin and ciprofloxacin increased mortality associated with B. anthracis Sterne infection, particularly in gamma-irradiated animals.


Outcomes and follow-up of patients treated for multidrug-resistant tuberculosis in Orel, Russia, 2002-2005.
Multidrug-resistant tuberculosis (MDR-TB) treatment facility, Orel Oblast, Russian Federation. To determine factors associated with poor outcome and to document status of patients after recording of TB outcomes. Retrospective review of prospective single cohort. Among 192 patients, factors significantly associated with poor outcome in multivariate analysis include three or more treatment interruptions during the intensive phase of therapy and alcohol or drug addiction (adjusted OR [aOR] 2.1, 95%CI 1.0-4.3 and aOR 1.9, 95%CI 1.0-3.7). Previous treatment was associated with poor outcome, but only among smear-positive patients (aOR 3.1, 95%CI 1.3-7.3). Ten patients (5%) developed extensively drug-resistant TB (XDR-TB) during treatment; of 115 patients with at least 6 months of follow-up data after outcomes were recorded, 13 (11%) developed XDR-TB. Interventions focused on supporting patient adherence during the intensive phase of treatment; the management of drug and alcohol addiction should be developed and studied. A substantial proportion of patients developed XDR-TB during and after treatment. Longer term follow-up data of patients treated for MDR-TB are needed to better inform programmatic policy.


Atomoxetine in abstinent cocaine users: Cognitive, subjective and cardiovascular effects.
No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement.


Protective effect of sialyllactose on the intestinal epithelium in weaned pigs upon enterotoxigenic Escherichia coli challenge.
Sialyllactose (SL), one of the most abundant oligosaccharides present in porcine breast milk, has been implicated in many biological functions, including the prebiotic and immune-modulating effects. This study was conducted to investigate the influences of dietary SL supplementation on intestinal barrier functions exposure to enterotoxigenic Escherichia coli (ETEC) in a porcine model. Thirty-two pigs were assigned to four treatments, fed with basal or SL-containing (5.0 g kg-1) diet, and orally infused with ETEC or culture medium. SL supplementation significantly reduced the diarrhea incidence and the abundance of E. coli in feces (P < 0.05). Interestingly, SL attenuated ETEC-induced intestinal epithelium injury as indicated by the decreased serum concentrations of diamine oxidase (DAO) and D-lactate and reduced the number of apoptotic cells in the jejunal epithelium (P < 0.05). Moreover, SL not only elevated the abundance of the tight-junction protein ZO-1 in the duodenal and ileal epithelium but also elevated the antioxidant capacity and the number of SIgA positive cells in the jejunal epithelium upon the ETEC challenge (P < 0.05). Importantly, SL decreased the expression levels of inflammation-related genes such as the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), myeloid differentiation factor 88 (MyD88) in the duodenum, and ileum upon ETEC challenge (P < 0.05). SL also significantly elevated the expression levels of two critical antioxidant genes such as the nuclear factor erythroid-2 related factor 2 (Nrf-2) and kelch-like ECH-associated protein 1 (KEAP-1) in the jejunum (P < 0.05). These results suggested that SL can alleviate ETEC-induced intestinal epithelium injury, which is associated with suppressed inflammation, improved intestinal immunity, antioxidant capacity, and improved intestinal epithelial functions.


Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors.
We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.


Genetic relationship between weaning weight and milk yield in Nguni cattle.
A study was conducted to estimate the genetic relationship between weaning weight and milk yield in Nguni cattle. Milk yield data (n=125) were collected from 116 Nguni cows from Mara Research Station located in Limpopo Province and Loskop South Farm located in Mpumalanga Province using the weigh-suckle-weigh technique. Weaning weight data (n=19 065) were obtained from stud Nguni cattle from 146 herds distributed throughout South Africa. Estimates of (co)variance components for milk yield and weaning weight were calculated using PEST and VCE softwares. The average weaning weight, age of the calf at weaning and 24-h milk yield was 158.94 kg, 210 days and 5.25 kg/day, respectively. Heritability estimates for milk yield, direct and maternal weaning weight were 0.22±0.238, 0.47±0.039 and 0.25±0.029, respectively. Estimates of genetic correlations for milk yield and maternal weaning weight, milk yield and direct weaning weight, direct and maternal weaning weight were 0.97±0.063, -0.71±0.416 and -0.56±0.247, respectively. The results indicate that maternal weaning weight is genetically highly predictive of milk yield in Nguni cattle. Maternal breeding values for weaning weight could therefore be used as a selection criterion to improve milk yield in Nguni cattle.


Catalyst- and solvent-free click synthesis of cyclodextrin-based polyrotaxanes exploiting a nitrile N-oxide.
A catalyst- and solvent-free synthesis of cyclodextrin-based polyrotaxanes exploiting a stable nitrile N-oxide as an end-capping agent was achieved. The C-C bond-forming end-capping reaction of an allyl-terminated pseudopolyrotaxane with the nitrile N-oxide proceeded smoothly by solid-state grinding in a mortar to afford a polyrotaxane.


Choroidal Thickness Variation According to Refractive Error Measured by Spectral Domain-optical Coherence Tomography in Korean Children.
To assess choroidal thickness (CT) variation according to refractive errors using enhanced-depth imaging optical coherence tomography. Eighty-nine eyes (in 89 children) <±6 diopter were categorized into three groups: hyperopia, emmetropia, and myopia, according to refractive error, and underwent choroidal scans using enhanced-depth imaging-optical coherence tomography. CT was measured at the fovea and at 1 mm and 3 mm nasal (N1 and N3), temporal (T1 and T3), superior (S1 and S3), and inferior (I1 and I3) from the fovea. Mean foveal CTs were 346.86 µm, 301.97 µm, and 267.46 µm in the hyperopia, emmetropia, and myopia groups, respectively (p < 0.05). CTs at N3 and T3 were 214.59 µm and 318.68 µm, 163.92 µm and 320.79 µm, and 153.93 µm and 295.61 µm in the hyperopia, emmetropia, and myopia groups, respectively (p < 0.05). All CTs in the hyperopia group were thicker than those of other groups (p < 0.05). Fovea was thickest and was significantly thicker than at N3 and I3 in hyperopia (p < 0.05). T3 thickness in the emmetropia and myopia groups was greater than thickness at other areas, particularly the nasal and inferior choroids (p < 0.05). CT was positively correlated with spherical equivalent (p = 0.029). In Korean children, CTs were greater in the hyperopia group than in the emmetropia and myopia groups. The temporal choroid was thicker than the nasal choroid, regardless of the refractive error. The thickest location in the hyperopia group was the fovea; however, the temporal choroid was thickest in the emmetropia and myopia groups.


Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway.
Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting. MA1 treatment showed potent cytotoxic activities on human colorectal cancer cells. MA1 treatment induced apoptosis by activating the poly(ADP-ribose) polymerase (PARP), caspase‑3, -7, and -9. MA1 treatment led to the increase in p53 upregulated modulator of apoptosis (PUMA) and the decrease in X-linked inhibitor of apoptosis protein (XIAP) and Survivin. In addition, MA1 treatment induced cell cycle arrest in the sub-G1 phase. The pan-caspase inhibitor, Z‑VAD‑FMK, attenuated these MA1-induced apoptotic effects on human colorectal cancer cells. Moreover, MA1 treatment suppressed tumor cell migration and invasion. The phosphorylation level of p38 was upregulated by MA1 treatment, and the inhibitor of p38, SB203580, attenuated the MA1-induced p38 phosphorylation as well as caspase‑3 and PARP activation. These results indicate that MA1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through the stimulation of the p38 signaling pathway.


Estimating and modelling the transmissibility of Middle East Respiratory Syndrome CoronaVirus during the 2015 outbreak in the Republic of Korea.
Emerging respiratory infections represent a significant public health threat. Because of their novelty, there are limited measures available to control their early spread. Learning from past outbreaks is important for future preparation. The Middle Eastern Respiratory Syndrome CoronaVirus (MERS-CoV ) 2015 outbreak in the Republic of Korea (ROK) provides one such opportunity. We demonstrated through quantitative methodologies how to estimate MERS-CoV's transmissibility and identified the effective countermeasures that stopped its spread. Using the outbreak data, statistical methods were employed to estimate the basic reproductive number R0 , the average number of secondary cases produced by a typical primary case during its entire infectious period in a fully susceptible population. A transmission dynamics model was also proposed to estimate R0 and to identify the most effective countermeasures. The consistency between results will provide cross-validation of the approaches. R0 ranged from 2.5 with 95% confidence interval (CI): [1.7, 3.1] (using the sequential Bayesian method) to 7.2 with 95% CI: [5.3, 9.4] (using the Nowcasting method). Estimates from transmission model were higher but overlapped with these. Personal protection and rapid confirmation of cases were identified as the most important countermeasures. Our estimates were in agreement with others from the ROK outbreak, albeit significantly higher than estimates based on other small outbreaks and sporadic cases of MERS-CoV. The large-scale outbreak in the ROK was jointly due to the high transmissibility in the healthcare-associated setting and the Korean culture-associated contact behaviour. Limiting such behaviour by rapidly identifying and isolating cases and avoiding high-risk contacts effectively stopped further transmission.


The association between park facilities and the occurrence of physical activity during park visits.
Prior research has found a positive relationship between the variety of park facilities and park-based physical activity (PA), but has not provided an estimate of the effect that additional different PA facilities have on whether an individual is active during a park visit. Using objective measures of park visits and PA from an urban sample of 225 adults in King County, Washington, we compared the variety of PA facilities in parks visited where an individual was active to PA facilities in parks where the same individual was sedentary. Each additional different PA facility at a park was associated with a 6% increased probability of being active during a visit. Adding additional different PA facilities to a park appears to have a moderate effect on whether an individual is active during a park visit, which could translate into large community health impacts when scaled up to multiple park visitors.


Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid.
Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel-Gruber syndromes. A mouse model lacking Tmem107 exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation. Tmem107 expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response to Smoothened agonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.


Parsing variance by marker type: Testing biogeographic hypotheses and differential contribution of historical processes to population structure in a desert lizard.
A fundamental goal of population genetic studies is to identify historical biogeographic patterns and understand the processes that generate them. However, localized demographic events can skew population genetic inference. Assessing populations with multiple types of genetic markers, each with unique mutation rates and responses to changes in population size, can help to identify potentially confounding population-specific demographic processes. Here, we compared population structure and connectivity inferred from microsatellites and restriction site-associated DNA loci among 17 populations of an arid-specialist lizard, the desert night lizard, Xantusia vigilis, in central California to test among historical processes structuring population genetic diversity. We found that both marker types yielded generally concordant insights into population genetic structure including a major phylogenetic break maintained between two populations separated by less than 10 km, suggesting that either marker type could be used to understand generalized demographic patterns across the region for management purposes. However, we also found that the effects of demography on marker discordance could be used to elucidate population histories and distinguish among competing biogeographic hypotheses. Our results suggest that comparisons of within-population diversity across marker types provide powerful opportunities for leveraging marker discordance, particularly for understanding the creation and maintenance of contact zones among clades.